Recent experiments in our laboratory indicate that two serogroups of tick transmitted viruses, Dhori (DHO) and Thogoto (THO), share a remarkable number of molecular features with established members of the Orthomyxoviridae. These enveloped, single-stranded RNA viruses contain seven unique genome segments. The genetic information of the viral RNA is encoded in the negative sense. The 3' terminal sequences are homologous with the 3' terminal sequences of influenza A, B and C viruses, suggesting a common evolutionary progenitor. In addition, we have sequenced 60% of a full-length cDNA clone of DHO segment 5 mRNA and have discovered a 23% amino acid sequence homology with the influenza family of nucleoproteins. While these viruses share a similar molelcular biology with the orthomyxoviruses, the adaptation of DHO and THO viruses to a mode of transmission involving an arthropod vector is a unique pathogenetic feature. We propose to examine four areas concerning the molecular biology of these viruses: 1) to determine the complete nucleotide sequences of DHO RNA segments 4, 5 and 6 from complete or near complete cDNA clones we have obtained; 2) to sequence the 5' termini of DHO matrix protein mRNAs isolated from infected cells to determine if nonviral template encoded heterologous oligonucleotides are present; 3) to test DHO interstrain reassortant viruses (which were derived from two parental strains of differing pathogenicities) for their pathogenic phenotypes in a neonatal mouse system; and 4) to determine if members of the THO serogroup of viruses are related to the DHO serogroup viruses by cross-hybridization studies. The discovery of viruses possessing molecular properties similar to those of influenza viruses yet possessing a dramatically altered pathogenesis and epidemiology provides the unusual opportunity to determine the molecular basis for these adaptations. We feel that these studies will contribute to an understanding of the unique molecular and biologic adaptations which allow the growth of these viruses in arthropod cells.